RT Journal
A1 Shen H, Damcott CM, Rampersaud E, et al
T1 FAmilial defective apolipoprotein b-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the old order amish
JF Archives of Internal Medicine
JO Archives of Internal Medicine
YR 2010
FD November 8
VO 170
IS 20
SP 1850
OP 1855
DO 10.1001/archinternmed.2010.384
UL http://dx.doi.org/10.1001/archinternmed.2010.384
AB Background
Elevated low-density lipoprotein cholesterol (LDL-C) levels are a major cardiovascular disease risk factor. Genetic factors are an important determinant of LDL-C levels.Methods
To identify single nucleotide polymorphisms associated with LDL-C and subclinical coronary atherosclerosis, we performed a genome-wide association study of LDL-C in 841 asymptomatic Amish individuals aged 20 to 80 years, with replication in a second sample of 663 Amish individuals. We also performed scanning for coronary artery calcification (CAC) in 1018 of these individuals.Results
From the initial genome-wide association study, a cluster of single nucleotide polymorphisms in the region of the apolipoprotein B-100 gene (APOB) was strongly associated with LDL-C levels (P < 10−68). Additional genotyping revealed the presence of R3500Q, the mutation responsible for familial defective apolipoprotein B-100, which was also strongly associated with LDL-C in the replication sample (P < 10−36). The R3500Q carrier frequency, previously reported to be 0.1% to 0.4% in white European individuals, was 12% in the combined sample of 1504 Amish participants, consistent with a founder effect. The mutation was also strongly associated with CAC in both samples (P < 10−6 in both) and accounted for 26% and 7% of the variation in LDL-C levels and CAC, respectively. Compared with noncarriers, R3500Q carriers on average had LDL-C levels 58 mg/dL higher, a 4.41-fold higher odds (95% confidence interval, 2.69-7.21) of having detectable CAC, and a 9.28-fold higher odds (2.93-29.35) of having extensive CAC (CAC score ≥400).Conclusion
The R3500Q mutation in APOB is a major determinant of LDL-C levels and CAC in the Amish.